NMDA receptor (NMDAr) activation allows Ca2+ flux across the membrane that induces spinal sensitization, activation of signal transduction cascades and hyperalgesia. However, activation of Ca2+ permeable non-NMDA receptors (Ca-permeable non-NMDAr), without any help from NMDAr, can also produce synaptic strengthening and activation of signal transduction cascades. Recent work using NMDAr antagonist-insensitive models of pain shows that intrathecal administration of a Ca2+ permeable non-NMDA receptor antagonist, blocks or reverses secondary mechanical allodynia. The same agent is without effect in some NMDA-sensitive (dependent) models of secondary hyperalgesia. This leads to the hypothesis: Ca2+ permeable AMPA receptor activation can induce spinal sensitization and hyperalgesia via an initiating mechanism distinct from NMDA receptor activation. A 3rd group of pain models is partially dependent on NMDAr activation. Thermal and mechanical hyperalgesia following intraplantar carrageenan are blocked equally well by either NMDA or Ca-permeable non-NMDAr antagonists. After capsaicin or C-fiber stimulation, ERK (member of the mitogen-activated protein kinase signaling cascade) and transcriptional factor CREB (cAMP responsive binding protein) become phosphorylated. However, less than half of the phosphorylation is blocked by NMDAr antagonist pretreatment. The remainder is elicited by agents acting on receptors other than NMDAr, perhaps including Ca-permeable non-NMDAr. If Ca-permeable non-NMDAr are responsible, this implies a convergence between NMDAr- and Ca-permeable non-NMDAr-induced pathways prior to ERK activation. As models of burn and post-surgical pain, in which Ca-permeable non-NMDAr presumably appears to play a role, resemble clinical conditions, this novel ionotropic pathway probably plays a significant part in generation of at least some clinical pain states. We propose to investigate the effects of Ca-permeable non-NMDAr activation on ERK and CREB phosphorylation (using Western blots and immunohistochemistry), expression of c-fos and development of hyperalgesia.